Ethanol selectively alters the function of neurotransmitter and neuromodulator receptors in the CNS. These changes may contribute to the acute, intoxicating effects of ethanol, and adaptations in receptor function may be associated with ethanol tolerance and/or physical dependence. Previous work showed decreased stimulation of cerebral cortical adenylate cyclase (AC) activity by beta- adrenergic agonists and guanine nucleotides, and decreased high- affinity beta-adrenergic agonist binding, in cerebral cortex of mice fed ethanol chronically. The data suggested an alteration in the properties of Gs, the stimulatory guanine nucleotide binding protein, in these mice. This hypothesis was supported by a demonstration of reduced stimulation of cerebral cortical AC activity by other agents that act through Gs in ethanol-fed mice, compared to controls, and reduced availability for cholera toxin- catalyzed ADP-ribosylation of a protein migrating like Gs on SDS- polyacrylamide gels. In contrast, there was no difference between control and ethanol-fed mice in pertussis toxin-catalyzed ADP- ribosylation of cerebral cortical proteins or, in initial studies, in the quantity of Go-alpha or Gi-alpha measured by Western blot analysis. Chronic ethanol ingestion thus appears to selectively affect the amount and/or function of one of a family of similar G proteins. The effects of ethanol on receptor-AC coupling are brain region-specific. Changes in beta-adrenergic agonist-stimulated AC activity and high-affinity agonist binding were similar in hippocampus and cortex of ethanol-fed mice, compared to controls, while little change was observed in cerebellum. This regional specificity was supported by autoradiographic analysis of high- affinity forskolin binding, which is believed to reflect binding to the Gs-alpha-AC complex. The regional specificity of the effects of ethanol on receptor-effector coupling may contribute to specific behavioral responses to chronic ethanol ingestion.